Keywords

6.1 Introduction

Parkinson’s disease (PD ) is a progressive neurodegenerative disorder clinically characterized by bradykinesia (slowness), rigidity (stiffness), resting tremor, and gait dysfunction with postural instability. The major pathological hallmark of PD is the degeneration of dopaminergic (DA) nigrostriatal neurons in the substantia nigra pars compacta (SNC) and the presence of cytoplasmic α-synuclein-positive inclusions (Lewy bodies) (Fearnley and Lees 1991; Forno 1996; Spillantini et al. 1998; Giasson et al. 2000; Dauer and Przedborski 2003). This progressive degeneration of the nigrostriatal system results in complex pathophysiological changes of neuronal activity and neurochemical imbalance in neurotransmitter release throughout the basal ganglia circuitry and their projection targets (Albin et al. 1989; DeLong 1990; Gerfen et al. 1990; Wichmann and DeLong 2006). The onset of parkinsonian motor symptoms appears only when a critical threshold of 50–60% DA neurons loss in SNC and 70–80% degeneration of striatal DA terminals have been reached (Hornykiewicz 1975, 1998). This lag between the development of motor deficits and the protracted extent of the nigrostriatal degenerative process provides an opportunity for neuroprotective intervention that could slow down the degeneration of the dopaminergic system and delay or prevent the development of parkinsonian motor symptoms .

Significant effort has, indeed, been devoted at identifying disease-modifying therapeutics in different animal models of PD. Unfortunately, despite encouraging preclinical data, none of these compounds were found to be neuroprotective when tested in human trials (Siderowf and Stern 2008; Schapira 2009a, b, c; Smith et al. 2012). Various potential explanations have been raised to explain the failure of these trials, including the lack of PD biomarkers and the late start of the neuroprotective therapy (Mandel et al. 2003, Schapira 2004, Siderowf and Stern 2008, Lang 2009, Olanow 2009, Rascol 2009, Schapira 2009a, c). Thus, the need for effective neuroprotective drugs that could alter the progressive degeneration of the dopaminergic nigrostriatal system and the development of PD biomarkers are key interrelated attributes to the successful development of effective neuroprotective therapy in PD.

Although the mechanisms that underlie nigral DA degeneration in PD remain poorly understood, evidence suggests that glutamate excitotoxicity contributes to the cascade of events that lead to DA cell death in the SNc (Fornai et al. 1997; Sonsalla et al. 1998; Greenamyre et al. 1999; Golembiowska et al. 2002; Blandini et al. 2004; Przedborski 2005). Glutamate elicits its action through the activation of ionotropic (iGlu) and metabotropic glutamate receptors (mGluRs). The use of compounds blocking iGlu, particularly of the N-methyl-D-aspartate (NMDA) subtype, has shown significant neuroprotective effects of midbrain dopaminergic neurons in experimental models of parkinsonism (Turski et al. 1991; Zuddas et al. 1991; Storey et al. 1992; Nash et al. 1999; Konitsiotis et al. 2000). However, the use of these compounds failed human trials because of narrow therapeutic windows and marked CNS side effects (Montastruc et al. 1992; Muir 2006). An alternative approach to the development of glutamate-mediated therapies with a good profile of safety and tolerability for brain disorders is the targeting of glutamate receptors that “modulate” rather than “mediate” fast excitatory synaptic transmission. Because the G-protein-coupled mGluRs meet these criteria, they have generated significant interest as new therapeutic targets for brain diseases, including symptomatic and neuroprotective agents in PD (Lovinger et al. 1993, Conn et al. 2005, Bonsi et al. 2007, Ossowska et al. 2007, Gasparini et al. 2008, Niswender and Conn 2010, Nicoletti et al. 2011, Finlay and Duty 2014, Nickols and Conn 2014, Williams and Dexter 2014, Amalric 2015, Nicoletti et al. 2015).

6.2 MGluR Localization in the Basal Ganglia Circuitry

Eight mGluR subtypes (mGluR1–mGluR8) have been cloned and divided into three groups (groups I–III) on the basis of sequence homologies, signal transduction pathways, and ligand-binding patterns (Pin and Duvoisin 1995; Conn and Pin 1997; Nakanishi et al. 1998; Anwyl 1999; Pin and Acher 2002). Members of these three groups of mGluRs are strongly expressed throughout the basal ganglia circuitry , where they regulate neuronal excitability and synaptic transmission via pre- and postsynaptic mechanisms (Calabresi et al. 1992, Lovinger et al. 1993, Lovinger and McCool 1995, Conn and Pin 1997, Pisani et al. 1997, Rouse et al. 2000, Smith et al. 2000, Pisani et al. 2001, Corti et al. 2002, Marino et al. 2002, 2003a, Gubellini et al. 2004, Conn et al. 2005, Johnson et al. 2009, Lovinger 2010). Furthermore, midbrain dopaminergic neurons in the SNc also express specific mGluRs which represent potential therapeutic targets for neuroprotection in PD (see below). Thus, the foundation of preclinical studies that have been performed so far to assess the potential relevance of mGluR-mediated neuroprotection in PD has been based on the assumption that excitotoxic effects upon midbrain dopaminergic neurons can be mediated either directly through overactivation of calcium-dependent postsynaptic glutamate receptors or via overactivity of glutamatergic inputs onto SNc neurons (Battaglia et al. 2002, 2004; Johnson et al. 2009; Masilamoni et al. 2011). In either case, drugs aimed at postsynaptic (i.e., group I) or presynaptic (i.e., groups II and III) mGluRs may have beneficial effects in reducing toxic insults upon midbrain dopaminergic neurons and possibly other vulnerable populations of neurons in PD (Johnson et al. 2009).

Group I mGluRs (mGluRs 1 and 5) are mainly expressed postsynaptically, couple to Gq proteins, and positively modulate neuronal excitability through activation of phospholipase C leading to an increase in intracellular Ca2+ and protein kinase C (Kim et al. 1994; Pin and Duvoisin 1995; Conn and Pin 1997; Fiorillo and Williams 1998; Nakanishi et al. 1998; Sala et al. 2005; Zhang et al. 2005), while group II (mGluRs 2 and 3) and group III (mGluRs 4, 6, 7, and 8) mGluRs are mainly localized presynaptically, classically couple to Gi/o, and negatively modulate neuronal excitability (Conn and Pin 1997). Group I mGluRs are largely expressed postsynaptically in dendrites and spines, where they enhance excitability through various postsynaptic mechanisms that involve regulation of intracellular calcium, functional interactions with NMDA receptors, and modulation of voltage-gated calcium channels (Conn and Pin 1997; Nakanishi et al. 1998; Alagarsamy et al. 1999; Pisani et al. 2001; Sala et al. 2005; Zhang et al. 2005)

On the other hand, group III mGluRs are predominantly located in the presynaptic active zones of glutamatergic and non-glutamatergic synapses, where they act as autoreceptors or heteroreceptors that reduce neurotransmitter release (Cartmell and Schoepp 2000; Ferraguti and Shigemoto 2006). Although mGluRs 4, 7, and 8 are expressed to a variable degree in different brain regions, mGluR6 is restricted to the retina (Vardi et al. 2000).

The two members of the group II mGluR subtypes , mGluR2 and mGluR3, are differentially expressed in neurons and astrocytes, respectively (Mineff and Valtschanoff 1999; Geurts et al. 2003). At the neuronal level, mGluR2 is located presynaptically in glutamatergic and non-glutamatergic terminals, but its pattern of subcellular expression is different from that of group III mGluRs; instead of being aggregated at the active zones close to the transmitter release sites, as is the case from group III mGluRs, mGluR2 is most commonly expressed away from the synapses, often in preterminal axonal segments, of glutamatergic and GABAergic afferents (Schoepp and Conn 1993; Pin and Duvoisin 1995; Conn and Pin 1997; Cartmell and Schoepp 2000; De Blasi et al. 2001; Galvan et al. 2006; Ferraguti et al. 2008; Niswender and Conn 2010). Thus, upon activation, groups II and III mGluRs can reduce glutamatergic signaling and dampen neuronal excitability giving them potential neuroprotective properties (Nicoletti et al. 1996). On the other hand, group I mGluR antagonists display neuroprotective properties, likely through reduced calcium release from intracellular stores and decreased neuroinflammation (Kim et al. 1994; Pin and Duvoisin 1995; Conn and Pin 1997; Nakanishi et al. 1998; Sala et al. 2005; Zhang et al. 2005).

In this review, we will discuss evidence for neuroprotective properties of different subtypes of mGluRs in PD. We will also summarize findings of mGluR-mediated neuroprotection in other brain diseases (Table 6.1). These will be followed by a brief discussion of the subtype-selective mGlu receptor ligands that still hold the promise to become disease-modifying drugs in neurodegenerative disorders.

Table 6.1 Studies that showed evidence of mGluR-mediated neuroprotection and anti-inflammatory effects in various brain diseases
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6.3 Neuroprotective Effects of Group I mGluRs

There is evidence that mice treated with the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) or mice that lack mGluR5 receptors show increased survival of nigrostriatal DA neurons after administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Battaglia et al. 2004; Aguirre et al. 2005; Armentero et al. 2006; Vernon et al. 2007). mGluR5 receptor antagonists are also protective against nigrostriatal dopamine denervation in the methamphetamine model of parkinsonism (Battaglia et al. 2002). The mGluR5 antagonist, MTEP, was also found to be neuroprotective against the loss of midbrain DA neurons and norepinephrine neurons in the locus coeruleus (LC) in a chronic MPTP -treated monkey model of PD (Masilamoni et al. 2011) (Fig. 6.1). In this study, we showed that neurons in the SNc and LC of monkeys chronically treated with low doses of MPTP over a period of over 20 weeks were significantly spared in animals that received daily administration of MTEP (Masilamoni et al. 2011). Altogether, these rodent and monkey data suggest that the use of mGluR5 receptor antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in PD. Taking into consideration evidence that mGluR5 antagonists also have significant anti-dyskinetic effects in rodent and nonhuman primate models of PD (Dekundy et al. 2006; Mela et al. 2007; Gravius et al. 2008; Levandis et al. 2008; Rylander et al. 2009; Johnston et al. 2010; Morin et al. 2010; Rylander et al. 2010; Gregoire et al. 2011) and some antiparkinsonian effects in 6-OHDA-treated rats (Breysse et al. 2002), these findings provide additional support for the potential use of mGluR5 antagonist as PD-relevant therapeutic.

Fig. 6.1
figure 1

Neuroprotective effects of MTEP towards MPTP-induced neurotoxicity of the midbrain dopaminergic nigrostriatal system in rhesus monkeys. (a–c) Coronal sections at the level of the pre-commissural striatum showing binding of the 18F-FECNT dopamine transporter ligand at baseline (a) and after chronic treatment with MPTP/vehicle (b) or MPTP/MTEP (C). (d–f) show corresponding levels of the striatum in the same groups of animals immunostained with a DAT antibody. (g–l) Coronal sections showing 18F-FECNT binding (g–i) or TH immunostaining (j–l) at the level of the Fig 6.1 (continued) ventral midbrain of the three animal groups used in this study. Abbreviations: PA associative putamen, CA associative caudate nucleus, AL limbic nucleus accumbens, SNC substantia nigra, PM motor putamen, CA associative caudate nucleus. Scale bar: 10 mm (applies to a–c and g–i) and 5 mm (applies to d–f and j–l). M: Densitometry analysis N. Stereological estimate of the total number of TH-positive neurons (means ± SD) in SNC-v, SNC-d and VTA regions of control, MPTP/vehicle and MPTP/MTEP treated monkeys. **p < 0.001 and *p< 0.05 for differences from control and MPTP/vehicle. #, p < 0.05 for differences between the vehicle and MTEP-treated animals. There were no significant difference found in the SNCd and VTA between control and MPTP/MTEP treated monkeys (see Masilamoni et al. 2011 for details)

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The evidence that various mGluR5 antagonists (AFQ056-mavoglurant; ADX-48621-dipraglurant) currently being tested in human trials as anti-dyskinetic drugs are well tolerated and do not worsen PD motor symptoms (Berg et al. 2011; Stocchi et al. 2013) is encouraging and provides further supports toward the chronic use of mGluR5-related compounds as potential neuroprotective drug in PD.

Although the exact mechanisms by which mGluR5 antagonists mediate their neuroprotective effects upon catecholaminergic neurons in toxin-based models of PD remain to be established, some interesting possibilities have been raised. In light of evidence that calcium dysregulation, mitochondrial respiration impairment, and excitotoxic insults contribute to the degeneration of nigral dopaminergic neurons in PD (Sherer et al. 2002; Maesawa et al. 2004; Wallace et al. 2007; Caudle and Zhang 2009; Chan et al. 2009; Cannon and Greenamyre 2010; Winklhofer and Haass 2010; Van Laar et al. 2011), the blockade of mGluR5 may provide its protective effects through reduction of intracellular calcium levels in dopaminergic neurons via decreased mGluR5-mediated activation of intracellular IP3 receptors (Kim et al. 1994; Pin and Duvoisin 1995; Conn and Pin 1997; Nakanishi et al. 1998; Sala et al. 2005; Zhang et al. 2005) and/or reduction of the potentiating effects of mGluR5 upon NMDA receptor function (Calabresi et al. 1992; Alagarsamy et al. 1999; Tu et al. 1999; Awad et al. 2000). An alternative mechanism could involve the reduction of overactive glutamatergic inputs from the subthalamic nucleus (STN) to SNC neurons in the PD state (Bezard et al. 1998; Rodriguez et al. 1998; Awad et al. 2000; Breysse et al. 2003; Fazal et al. 2003; Shimo and Wichmann 2009; Piallat et al. 2011). Finally, because glial mGluR5 expression is upregulated in some inflammatory processes (Byrnes et al. 2009a; Loane et al. 2009, 2012; Drouin-Ouellet et al. 2011), the blockade of these receptors may reduce these harmful effects and attenuate MPTP-induced toxicity toward midbrain dopaminergic neurons (see further discussion below).

6.4 Neuroprotective Effects of Group II mGluRs in PD

Results from several groups reveal a moderate neuroprotective effect of Group II mGluR agonists in rodent models of PD, the magnitude of which was dependent on lesion severity (Battaglia et al. 2002, 2003, Murray et al. 2002; Vernon et al. 2005; Battaglia et al. 2009). Both mGluR2 and mGluR3 are expressed in the BG circuitry including in STN neurons (Testa et al. 1994). Activation of presynaptic group II mGluRs at the STN-SNc synapse reduces excitatory postsynaptic current amplitudes in rat SNc neurons (Bradley et al. 2000; Wang et al. 2005). In line with these observations, systemic treatment or intranigral administration of the group II mGluR agonists LY379268 and (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) reduces the extent of 6-OHDA-induced toxicity of dopaminergic neurons in the rat SNc (Murray et al. 2002; Vernon et al. 2005; Chan et al. 2010). In addition, activation of group II mGluRs by dual mGlu2/3 receptor agonist LY379268 or DCG-IV reduces SNc degeneration in mice after intrastriatal MPP+ or systemic MPTP administration, further supporting a role for group II mGluRs as disease-modifying agents in PD (Battaglia et al. 2003). Activation of mGluR2/3 could also contribute to neurorestoration via the production and release of neurotrophic factors from glial cells in vitro (Bruno et al. 1998a; D’Onofrio et al. 2001) and in vivo (Matarredona et al. 2001; Corti et al. 2007; Battaglia et al. 2009). Through the use of the mGluR2/3 receptor agonist LY379268 in mGluR2 and mGluR3 receptor knockout mice, Corti et al. (2007) suggested that the neuroprotective properties of the mGluR2/3 receptor agonist LY379268 in MPTP-treated mice were entirely mediated by activation of the astrocytic mGluR3 receptor and that these effects were amplified in the absence of neuronal mGluR2 receptors, suggesting that mGluR2 activation might be harmful to toxin exposure (Corti et al. 2007). The studies of the neuroprotective properties of the selective mGluR3 receptor agonist, N-acetylaspartylglutamate (NAAG) (Orlando et al. 1997; Wroblewska et al. 1997; Bruno et al. 1998a; Bergeron et al. 2005), have been limited by the poor blood-brain barrier permeability for this compound (Westbrook et al. 1986; Sekiguchi et al. 1992).

6.5 Neuroprotective Effects of Group III mGluRs in PD

Several lines of evidence based on cellular and physiological data predict that activation of group III mGluRs in the BG could have neuroprotective effects in PD (Wigmore and Lacey 1998; Valenti et al. 2002, 2003, 2005). These Gi/Go-coupled auto- or heteroreceptors regulate GABAergic and glutamatergic synaptic transmission, most likely through inhibition of voltage-gated calcium entry required for triggering transmitter release (Trombley and Westbrook 1992; Conn and Pin 1997). In regard to neuroprotection in PD, activation of mGluR4 at the striatopallidal synapse reduces the activity of the indirect pathway, which attenuates hyperactivity of the STN, and thereby reduces its excitotoxic effects toward SNc dopaminergic neurons (Valenti et al. 2005). Group III mGluRs activation protects against NMDA-induced toxicity in cultured neurons and in vivo, neuroprotection against excitotoxic insult (Gasparini et al. 1999; Bruno et al. 2000; Flor et al. 2002).

Consistent with the prediction that group III mGluRs activation might have neuroprotective effects in PD, both acute and subchronic intranigral infusion of the group III mGluRs agonist L-AP4 reduce the extent of 6-OHDA toxicity in the rat SNc (Vernon et al. 2005, 2007, 2008; Jiang et al. 2006; Betts et al. 2012). Furthermore, systemic or intrapallidal administration of the mGluR4 allosteric potentiator, PHCCC (Phenyl-7-(hydroxyimino) cyclopropa [b] chromen-1a-carboxamide), reduces the extent of nigrostriatal MPTP toxicity in wild-type mice, but not in mice lacking mGluR4, further supporting the selective activation of mGluR4 as a neuroprotective approach in PD (Battaglia et al. 2006). The study of mGluR7 and mGluR8 receptor subtypes in neuroprotection awaits the development of specific compounds that selectively regulate these receptors.

6.6 Neuroprotective Effects of mGluR-Related Drugs in Other Brain Diseases

Chronic treatment with the prototypic mGluR5 receptor antagonist, MPEP, attenuates cell death, delays the onset of motor symptoms, and prolongs survival in mutant mice carrying a mutation of SOD1 associated with familiar ALS (Rossi et al. 2008). There is evidence that modulation of mGluR1 and mGluR5 on oligodendrocytes is protective in a rodent model of periventricular leukomalacia during the developmental peak of vulnerability to hypoxia/ischemia, and modulation of these receptors is protective in a rodent model of periventricular leukomalacia (Jantzie et al. 2010). Recent evidence from Huntington’s disease (HD) mouse model indicates that the mGluR5 allosteric potentiator, CDPPB, protects striatal neurons against excitotoxic neuronal death, maybe through activation of Akt pathway, without triggering increased intracellular Ca2+ concentration (Ribeiro et al. 2010; Doria et al. 2013, 2015). There is also evidence that the mGluR5 antagonist MPEP might reduce disease progression in HD mouse models (Schiefer et al. 2004; Ribeiro et al. 2011).

6.7 Anti-inflammatory Properties of mGluRs: Implications for Neuroprotection

In the normal brain, microglia , the resident CNS macrophages, are found in a resting state with ramified morphology, but when chronically activated in response to insults, they display an amoeboid morphology (Kreutzberg 1996; Nimmerjahn et al. 2005) and exacerbate neurodegeneration by releasing glutamate and neurotoxic pro-inflammatory cytokines and cytotoxic factors (Barger and Basile 2001; Parker et al. 2002; Cunningham et al. 2005; Barger et al. 2007; McCoy and Tansey 2008; Lee et al. 2009; Tansey and Goldberg 2010). In addition, prolonged activation of microglia prevents them from carrying out their neuro-supportive functions such as the release of key growth factors (Benoit et al. 2008). Microglial toxicity toward midbrain dopaminergic neurons is well documented in a number of cell culture studies and animal models of PD (Gao et al. 2002a, b; Liu and Hong 2003; McCoy and Tansey 2008; Lee et al. 2009; Tansey and Goldberg 2010; Barnum et al. 2014). It has been postulated that both the initiation and progression of PD are triggered by neuroinflammation (Qin et al. 2007a, b; McCoy and Tansey 2008; Lee et al. 2009; Tansey and Goldberg 2010) and there is a growing body of evidence that in some cases, PD is linked to head trauma, viruses, and infections which subsequently trigger microglial activation (Liu and Hong 2003; Herrera et al. 2005). Inflammation is also heavily implicated in the pathogenesis of other neurodegenerative diseases including AD, ALS, MS, and HD (McGeer and McGeer 2002; Kutzelnigg et al. 2005; Solomon et al. 2006; Gao and Hong 2008; Hickman et al. 2008; Jimenez et al. 2008; Moller 2010).

As discussed above, glia (astrocytes, microglia, and oligodendrocytes) express mGluRs to variable degrees. Although mGluR3 is the most abundant subtype of glial mGluRs, there is evidence that groups I and III mGluRs also display light glial expression. These glial receptors are activated under normal and pathophysiological conditions (Loane et al. 2012). The selective mGluR5 orthosteric agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), reduces microglial activation and the associated release of pro-inflammatory mediators following stimulation with either lipopolysaccharide (LPS) or interferon-γ (IFNγ) (Byrnes et al. 2009a, b; Loane et al. 2009). CHPG treatment also attenuates NADPH oxidase (NOX2) activity levels and abolishes the neurotoxic potential of activated microglia in microglia/neuron co-culture models. The anti-inflammatory effects of CHPG are abolished in mGluR5 knockout mice or by addition of the mGluR5 antagonist, MTEP, demonstrating selective mGluR5-mediated neuroprotective effects through microglia (Byrnes et al. 2009a; Loane et al. 2009). Recently, mGluR5 positive allosteric modulators were found to significantly attenuate both LPS- and IFNγ-induced nitric oxide (NO) and tumor necrosis factor-α (TNFα) release in cultured microglia with higher potency compared to the orthosteric agonist, CHPG (Xue et al. 2014). These data support the use of mGluR5 PAMs as anti-inflammatory neuroprotective agents. MGluR5 PAMs are currently being investigated as potential treatment for various CNS conditions ranging from schizophrenia and anxiety disorders (Kinney et al. 2003, 2005; Homayoun et al. 2004; Lecourtier et al. 2007; Gravius et al. 2008) to learning and cognition-related problems (Gravius et al. 2008; Ayala et al. 2009; Gass and Olive 2009; Cleva et al. 2010; Reichel et al. 2011). Whether their neuroprotective/anti-inflammatory properties contribute to the potential benefit of these compounds in these disorders remain to be established.

Activation of group III mGluRs also mediates anti-inflammatory effects. For example, LPS-induced microglial activation in vitro is attenuated by the group III mGluR agonists L-AP4 and RS-PPG (Taylor et al. 2003). Activation of glial mGluR4 reduces the production of RANTES, a chemokine involved in neuroinflammation that circulates at higher levels in humans with PD compared with age- and sex-matched controls (Besong et al. 2002; Rentzos et al. 2007). L-AP4 is similarly protective against myelin-induced microglial neurotoxicity in cell culture, a finding attributable to the mGluR-mediated inhibition of soluble toxin production by activated microglia (Pinteaux-Jones et al. 2008). Similarly, oligodendrocyte precursor cells found in lesion sites are particularly vulnerable to cytotoxic and pro-inflammatory factors released by activated microglia, and stimulation of group III mGluRs by L-AP4 prevents microglial-induced inhibition of oligodendrocyte precursor cell proliferation (Taylor et al. 2010). These studies suggest that targeting microglia by group III mGlu receptors has the potential to encourage neuroprotection and regeneration of lost myelin in MS.

Activation of mGluR2/3 stimulates the production and release of neurotrophic factors from glial cells in vitro (Bruno et al. 1998b; D’Onofrio et al. 2001) and in vivo (Matarredona et al. 2001; Corti et al. 2007; Battaglia et al. 2009). Results from several groups reveal a moderate neuroprotective effect of group II mGluR agonists in rodent models of PD, the magnitude of which was dependent on lesion severity (Battaglia et al. 2002, 2003, 2009, Murray et al. 2002; Vernon et al. 2005; ).

6.8 mGluR-Mediated Neuroprotection vs Disease Biomarkers

The mGluRs are therapeutic targets of great interest for various brain diseases (Conn et al. 2005; Marino and Conn 2006; Johnson et al. 2009; Niswender and Conn 2010). Their beneficial symptomatic effects are further amplified by their potential neuroprotective properties in PD and other brain diseases . However, caution must be exercised in translating the promising preclinical neuroprotective data discussed in this review to human trials (Olanow 2009; Smith et al. 2012; Schapira et al. 2014). The constant failure of previous neuroprotective human trials in PD patients (Olanow 2009) indicates that the effective assessment of mGluR neuroprotective properties in PD must await the development of biomarkers that will allow to identify at-risk candidates for the disease prior to the appearance of motor symptoms. We hope that the current effort of the Parkinson Progression Marker Initiative (PPMI) multicenter study (Parkinson Progression Marker 2011) will help identify reliable progression biomarkers that could be used toward the future assessment of the disease-modifying properties of mGluRs in PD.